Biomineralized nanomedicine for enhanced cancer therapy through in situ toxification and amplified Ca2+ overload

Disulfiram (DSF), an FDA-approved drug for alcoholism, has demonstrated promising anti-tumor effects combined with Cu2+. This combination is achieved through the metabolism of DSF into dithiocarbamate (DTC), which chelates with Cu2+ to form the active form of DTC-copper complexes (CuET). Interestingly, our investigation revealed that Ca2+ can serve as another amplifier to enhance the efficacy of DSF by inducing calcium overload in tumor cells. Building upon this finding, we developed biomineralized nanoparticles (CuCaP@DTC) capable of controlled release of DTC, Cu2+, and Ca2+ in response to the acidic tumor microenvironment. These nanoparticles exhibited stability in the bloodstream for prolonged circulation, enabling their passive accumulation in tumors while efficiently releasing Ca2+ and Cu2+/DTC to facilitate CuET generation within tumor cells. The combined effect of in-situ CuET generation and calcium overload resulted in amplified anti-tumor effects. This research underscores the potential of synergistically combining DSF, copper, and calcium as a promising approach for improving treatment outcomes. Furthermore, it emphasizes the importance of rational design in delivery carrier systems based on a comprehensive understanding of the therapeutic mechanisms to enhance the drug efficacy.